1. Field of the Invention
The present invention relates to a novel morpholine derivative or a salt thereof having an ATM (ataxia telangiectasia mutated) inhibitory action.
2. Description of the Related Art
ATM consists of 3056 amino acids that have been identified as a gene responsible for ataxia telangiectasia (A-T), and is a serine/threonine kinase of about 350 kDa belonging to a PI3K (Phosphoinisitide 3-kinase) family (The Journal of biological chemistry, Vol. 274, pp. 25571-25575). ATM senses DNA double-strand break (DSB) induced in the cells by irradiation with an ionizing radiation or by a certain type of anticancer agent treatment, and serine 1981 is autophosphorylated, and as a result, becomes an activator. It is known that the phosphorylated ATM performs a homologous recombination, repairs DSB, and phosphorylates a downstream protein such as Chk2 or p53, and as a result, arrest of a cell cycle, induction of a DNA repair factor, or the like is suppressed (The Journal of biological chemistry, Vol. 274, pp. 25571-25575, 1999; Nature, Vol. 421, pp. 499-506, 2003; EMBO Journal, Vol. 19, pp. 463-471, 2000; and The Journal of biological chemistry, Vol. 274, pp. 31463-31467, 1999). In an A-T patient, ATM inactivation mutation is observed, and, as clinical symptoms, progressive cerebellar degeneration, oculocutaneous telangiectasia, delay of growth, immunodeficiency, predisposition of cancer, and premature senility are observed. In addition, at a cellular level, high sensitivity to an ionizing radiation or a treatment having effects similar to the ionizing radiation is observed (Science, Vol. 268, pp. 1749-1753, 1995). Based on the above description, it is expected that the compound having an ATM inhibitory action has an action of enhancing the effects on a cancer cure in which an ionizing radiation or an anticancer agent having effects similar to the ionizing radiation is applied. On the other hand, nerve cells in which ATM is deficient exhibit resistance to apoptosis through p53 induced by radiation (Science, Vol. 280, pp. 1089-1091, 1998), and thus, in a certain type of cell including nerve cells, there is a possibility that a radiation protection ability is exhibited. In addition, by exhibiting temporary immunodeficiency caused by the compound having an ATM inhibitory action, there is a possibility that the action of a disease in which an immune function is involved is reduced.
It is known that, when a retrovirus introduces its DNA produced by reverse transcription into a host cell, the retrovirus uses an ATM function of the host (Molecular Cell Biology, Vol. 21, pp. 1164-1172, 2001). Thus, it is expected that the compound having an ATM inhibitory action is useful in the prevention and cure of a disease caused by retroviral infection.
It is reported that ATM is involved in functional maintenance or proliferation through an ATM downstream signal, alone or by an interaction with other proteins (Nature, Vol. 431, pp. 997-1002, 2004; Blood, Vol. 119, pp. 180-187, 2012). Thus, it is expected that, by a use of an ATM inhibitor alone or by a combined use with an inhibitor to a protein that interacts with the ATM, cell killing effects are exhibited in a certain type of cancers.
It is reported that, in precancerous lesion in an onset process of cancer, expression of activated ATM is observed (Clinical Cancer Research, Vol. 15, pp. 4371-4377, 2007). It is thought that, by the cell killing effects of immune cells or active cell proliferation in a carcinogenic process, DNA repair through ATM is performed. Thus, it is expected that, in the period of a carcinogenic process, cancer onset can be prevented by a compound having an ATM inhibitory action.
On the other hand, a morpholine derivative having ATM inhibitory activity is known (WO2005/016919A).